EP3007683B1 - Composition for oral administration of magnesium, in association with a composition for the treatment of type 2 diabetes and its complications - Google Patents

Description

Field of the invention

The present invention relates to a composition for oral administration comprising magnesium, for use in the treatment of type 2 diabetes or its complications, in combination with a composition for treating type 2 diabetes or its complications. The composition comprising magnesium is more specifically in the form of a sustained release tablet. The invention is as defined in the appended claims.

Prior art

We know, especially patent applications WO 01/22943 , US 6887492 , US 5849338 and GB 1356097 illustrating the prior art, which has been proposed in the past technical solutions to provide magnesium release time-shifted.

Furthermore, with regard to the oral compositions of magnesium extended-release, the European patent is known EP 0542979 and international applications WO 2004/105778 and WO 2009/150323 .

Magnesium, in the form of hydrate, hydrated oxide, carbonate, chloride and other salts, is widely used in the form of food supplements and / or drugs. The magnesium ion Mg ²⁺ plays a very important role in the ionic balance of the human body, in particular it plays a role in many enzymatic reactions involved in metabolic processes in humans. Magnesium levels in the plasma of healthy people are relatively constant, with a reference range for total serum levels of 0.75-0.96 mmol / L. A number of hormones including parathyroid hormone (PTH) and calcitonin, vitamin D, glucagon, antidiuretic hormone, aldosterone, sex steroids and insulin have been described as influencing magnesium balance ( NE Saris et al. Magnesium. Year update on Physiological, Clinical and Analytical aspects, Clinica chimica acta; International Journal of Clinical Chemistry, 294 (2000), 1-26 ). Insulin stimulates renal reabsorption of magnesium in the ascending limb of Henle's loop. Thus, insulin deficiency directly affects the transport of magnesium in addition to developing a ketoacidosis that inhibits the maintenance of magnesium ( GA Quamme, Renal Magnesium Handling: New Insights in Understanding Old Problems, Kidney International, 52 (1997), 1180-1195 ).

Many disorders may be associated with a lack of magnesium: depression and anxiety, diabetes, muscle spasms, cramps, cardiovascular disorders, high blood pressure, insomnia and osteoporosis. Magnesium actively participates in the transmission of nerve impulses between neurons. The recommended daily intake of magnesium in Europe is estimated at 375 mg per day (double for athletes or pregnant women) or about 6 mg per kg of body weight.

Taking magnesium supplement is common in the form of drugs or dietary supplements. The latter use different salts (for example: chloride, carbonate, pidolate, aspartate, citrate, lactate, malate, threonate) or oxides and are presented in different galenical forms (for example solution, capsule, tablet) with in their composition one or more of these salts. These different galenic forms on the market can offer different types of magnesium release in the body: immediate release, delayed release or sustained release.

The body does not produce magnesium. It consumes more or less quickly depending on physical activity and stress. It must therefore draw on daily food and supplements of this diet if necessary. Excessive consumption of magnesium is naturally eliminated by the body in the urine. Magnesium does not accumulate. Ingestion of large amounts of magnesium causes a laxative effect or purgative. Excess magnesium intoxication may occur in children and in the case of someone with kidney failure.

Diabetes mellitus or more generally diabetes is a disease caused by a deficiency or a decrease in the effectiveness of endogenous insulin. This metabolic disease is characterized by elevated blood sugar or glucose levels either because the pancreas does not produce enough insulin (type 1 diabetes) or because the cells do not respond properly to the insulin produced ( Type 2 diabetes).

Many findings suggest that higher magnesium intake may reduce the incidence of diabetes. A meta-analysis by Dong et al. has provided evidence that magnesium intake is inversely proportional to the risk of developing type 2 diabetes in a dose-dependent manner ( Jia-Yi Dong et al. "Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies, diabetes care, 34 (2011), 2116-2122 ). Y. Song et al. (Diabetic medicine, 2006, 23 (10), 1050-1056 ) also reviewed clinical studies of the effects of magnesium oral supplementation on glycemic control in type 2 diabetes. This suggests that magnesium is one of the nutrients involved in the prevention of diabetes. The link between magnesium and diabetes mellitus has already been described. Studies have shown that average plasma and intracellular free magnesium levels are lower in diabetic patients than in the general population. Hypomagnesemia occurs in 13.5% to 47.7% of patients with type 2 diabetes compared to 2.5% to 15% of people without diabetes. Patients with diabetes mellitus often have a magnesium deficiency, which may be associated with insulin resistance (characteristic of patients with type 2 diabetes). It has also been found that magnesium improves the insulin response to dietary sugar and improves the action of insulin by regulating blood sugar levels.

With regard to the complications of diabetes such as cardiovascular diseases, magnesium supplements with MgCl2 have been shown to reduce blood pressure in hypertensive diabetic adults with hypomagnesemia.

With respect to retinopathy caused by diabetes, some studies have shown that patients with retinopathy have a lower average plasma magnesium concentration than patients without retinopathy ( P McNair and others, 'Hypomagnesemia, a Risk Factor in Diabetic Retinopathy', Diabetes, 27 (1978), 1075-1077 ).

Nephropathy is one of the most common complications of diabetes. Low levels of magnesium in serum have been reported to be associated with a faster decline in renal function in patients with type 2 diabetes mellitus ( PC Pham and others, 'The Link Between Lower Magnesium Serum and Kidney Function in Patients with Mellitus Diabetes Type 2 Deserves a Closer Look', Clinical nephrology, 71 (2009), 375-379 ; PCT Pham and others, 'Lower Serum Magnesium Levels Are Associated with More Rapid Decline of Renal Function in Patients with Diabetes Mellitus Type 2', Clinical Nephrology, 63 (2005), 429-436 ).

Researchers have shown the efficacy and safety of MgCl ₂ for the treatment of depression in elderly patients with type 2 diabetes and hypomagnesemia ( Lazaro Barragán-Rodríguez, Martha Rodríguez-Morán and Fernando Guerrero-Romero, 'Efficacy and Safety of Oral Magnesium Supplementation in the Treatment of Depression in the Elderly with Type 2 Diabetes: a Randomized Equivalent Trial', Magnesium research: official organ of the International Society for the Development of Research on Magnesium, 21 (2008), 218-223 ).

It has also been observed that magnesium deficiency is present and related to the presence of foot ulcers in patients with type 2 diabetes mellitus ( M Rodríguez-Morán and F Guerrero-Romero, 'Low Serum Magnesium Levels and Foot Ulcers in Subjects with Type 2 Diabetes', Archives of Medical Research, 32 (2001), 300-303 ).

It is therefore reasonable to assume that magnesium satiety can delay the onset of diabetes, reduce its effects, and potentially prevent its serious complications, such as cardiovascular disease, retinopathy, nephropathy, depression, and ulcers. foot.

Thus, a magnesium supplement in patients with type 2 diabetes could possibly be beneficial. However, long-term treatment with a high magnesium dose may cause side effects that are clinically relevant to patient compliance, particularly in patients with renal impairment.

Despite the remarkable progress made in the field of diabetes and its complications, it remains necessary to find new treatments or combinations of drugs that are effective for the treatment of diabetes and have minimal side effects and / or toxic. Diabetes is a chronic disease that can be controlled. The disease represents a loss of freedom with a strict regime to follow, a loss of safety (example hypoglycemia crisis) and unpredictable complications. To limit the risk of complications, you must scrupulously control your diabetes, follow your treatment and the advice of your doctor. Thus, magnesium is one of the elements that could improve the quality of life of the diabetic patient. However, there are many formulas or compositions containing magnesium (drugs or dietary supplements) on the current market but they may not all be adapted to the needs of the diabetic patient.

As such, it has been identified by the Applicant that the combination of a particular composition based on magnesium and a pharmaceutical composition comprising at least one pharmaceutical active ingredient for treating type 2 diabetes or its complications makes it possible to obtain a therapeutic treatment for type 2 diabetes and its particularly effective complications, without having side effects related to the intake of magnesium. The composition which will be described below has many advantages, since it makes it possible in particular not to interact with the treatment of diabetes, to be effective in improving the physiological parameters related to diabetes, to be able to be used for a long time. to correct a magnesium deficiency (allowing in particular a plasma level of constant Mg without peak blood), to have a good bioavailability, to be well tolerated intestinal and without side effects, to present a chemical formulation and dosage reducing the renal elimination of Mg, and to present a formulation to reduce the risk of hypermagnesemia in case of nephropathy or renal failure.

Thus, the applicant proposes a composition comprising magnesium, which is in particular at low dose and extended release, for use in the treatment of type 2 diabetes or one of its complications, in combination with a pharmaceutical composition comprising less an active ingredient for the treatment of type 2 diabetes. Thus, the particular composition comprising magnesium makes it possible to maintain a relatively constant magnesium level in the body (for example, all along said treatment, days and nights), without causing side effects due in particular to too high doses of magnesium in the blood.

Object of the invention

According to a first aspect of the invention, there is provided a composition comprising magnesium, which is particularly low-dose and prolonged-release, for use in the treatment of type 2 diabetes or one of its complications, in combination with a pharmaceutical composition comprising at least one active agent for the treatment of type 2 diabetes. More specifically, said compositions are administered simultaneously, separately or spread over time. The composition comprising magnesium is administered such that 100 to 200 mg of magnesium per day is administered to a subject.

• (A) 90 à 110 parties en poids de magnésium, la source de magnésium étant présente sous la forme choisie parmi MgO, MgCl₂ et les hydrates de formule MgCl₂.n(H₂O) où n est un nombre réel supérieur à 0 et inférieur ou égal à 6,
• (B1) 180 à 190 parties en poids d'hydroxypropylméthylcellulose,
• (B2) 19,8 à 22,2 parties en poids de béhénate de glycéryle,
• (C1) 10 à 12 parties en poids de lactose, et
• (C2) 10 à 12 parties en poids de silice colloïdale ;

ladite composition comprend également un enrobage, qui n'est pas un enrobage gastrorésistant, mais un enrobage de protection ralentissant la dissolution du Mg au niveau gastrique.More specifically, the composition comprising magnesium is a composition for oral administration, in tablet form, comprising a magnesium matrix with progressive release, which forms in particular a core, said matrix comprising, or in particular consisting of, magnesium, a hydrophilic retarding agent (B1), a hydrophobic retarding agent (B2), an inert filler (C1) acting as a diluent and an inert filler (C2) acting as a lubricating means, said matrix being characterized in that that it includes, or in particular, consisting of:

• (A) 90 to 110 parts by weight of magnesium, the magnesium source being present in the form selected from MgO, MgCl ₂ and hydrates of formula MgCl ₂ .n (H ₂ O) where n is a real number greater than 0 and less than or equal to 6,
• (B1) 180 to 190 parts by weight of hydroxypropylmethylcellulose,
• (B2) 19.8 to 22.2 parts by weight of glyceryl behenate,
• (C1) 10 to 12 parts by weight of lactose, and
• (C2) 10 to 12 parts by weight of colloidal silica;

said composition also comprises a coating, which is not a gastroresistant coating, but a protective coating slowing the dissolution of Mg at the gastric level.

The coating of the matrix (ie the coating of the naked tablet) is not gastroresistant. It intervenes to protect it, especially during packaging and storage, on the one hand, and it serves to slow the release of magnesium gastric level, on the other hand. According to a particular embodiment, it represents 15 to 75 parts by weight for an amount of 90 to 110 parts by weight of Mg (ie approximately 1.3 to 7.5% by weight relative to the weight of the matrix, ie that is, the naked tablet).

The rate of dissolution (δ) of magnesium (expressed in% relative to the total magnesium supplied by the magnesium source) was determined in vitro . The coated matrix according to the invention provides, after 2 hours in 0.1N HCl medium, a dissolution rate δ which is less than or equal to 60%, preferably between 20% and 60%.

When it is desired to appreciate the overall kinetics of in vitro dissolution of a tablet, a conventional dissolution system (hereinafter referred to as "dissolution system A") is used first in an acid medium [advantageously 900 ml according to the American Pharmacopoeia ] 0.1N HCl from T = 0 to T = 2h (ie treatment corresponding approximately to the transit time in the stomach), then in a buffer [advantageously 900 ml] at pH 6.8 from T = 2h to T = 8h, in order to determine the cumulative levels of dissolved active substance, in this case magnesium, at the instants T = 2h, T = 4h, T = 6h and T = 8h [ie treatment corresponding approximately to the transit time in the small intestine ( from T = 2h to T = 4h) then treatment corresponding approximately to the transit in the large intestine (from T = 4h to T = 8h)]. This dissolution kinetics is determined at a temperature which can be from room temperature (15-25 ° C) up to 40 ° C. As in the present invention the coated tablet and its components are all storage stable for several months at 40 ° C, the dissolution kinetics was measured here at 40 ° C for convenience to be placed in temperature conditions substantially similar to that from inside the human body.

• à T = 2h, on a : δ ≤, 60 %, plus précisément : 20 % ≤ δ ≤ 60 %, et de préférence : 25 % ≤ δ ≤ 58 % ;
• à T = 4h, on a : δ ≤ 85 %, plus précisément : 40 % ≤ δ ≤ 85 %, et de préférence : 45 % ≤ δ ≤ 82 % ;
• à T = 6h, on a : δ ≤ 98 %, plus précisément : 60 % ≤ δ ≤ 98 %, et de préférence : 80 % ≤ δ ≤ 95 % ; et
• à T = 8h, on a : δ ≤ 100 %, plus précisément : 90 % ≤ δ ≤ 100 %, et de préférence : 95 % ≤ δ ≤ 99,9 %.

The coated tablet used in the composition according to the invention has a dissolution profile such that:

• at T = 2h, we have: δ ≤, 60%, more precisely: 20% ≤ δ ≤ 60%, and preferably: 25% ≤ δ ≤ 58%;
• at T = 4h, we have: δ ≤ 85%, more precisely: 40% ≤ δ ≤ 85%, and preferably: 45% ≤ δ ≤ 82%;
• at T = 6h, we have: δ ≤ 98%, more precisely: 60% ≤ δ ≤ 98%, and preferably: 80% ≤ δ ≤ 95%; and
• at T = 8h, we have: δ ≤ 100%, more precisely: 90% ≤ δ ≤ 100%, and preferably: 95% ≤ δ ≤ 99.9%.

Thus, the composition comprising magnesium used in the present invention advantageously has a dissolution which (i) begins in the 'gastric' phase (from T = 0 to T = 2h) with slowed dissolution kinetics [the dissolution rate ( δ) magnesium compared to the magnesium administered through the magnesium source] being less than or equal to 60%], which allows the magnesium to arrive at spun dose in the small intestine where it begins to be absorbed with low kinetics (from T = 2h to T = 4h), on the one hand, then to arrive in the 'large intestine' phase (from T = 4h to T = 8h), on the other hand. The composition used according to the invention therefore has the advantage of being extended-release. The term "sustained release" or "progressive release" of magnesium therefore corresponds to a continuous release of magnesium in biological form; the whole being absorbed by the body over a period of 8 hours from the ingestion of tablet.

Thus, the composition comprising magnesium has the advantage of a preferential absorption of Mg ²⁺ at the level of the ileum, where the absorption of Mg is maximal, and a slower and progressive dissolution, which is programmed, of the exit of the stomach to the large intestine. The release of magnesium in the form Mg ^{2+ is} advantageously continuous throughout the gastrointestinal tract of the stomach to the large intestine, while the absorption of magnesium (always in the form Mg ²⁺ ) is all along from the intestinal tract of the duodenum to the large intestine, the absorption being maximal at the level of the ileum (ie the last part of the small intestine).

• une matrice (formant en particulier un noyau) comprenant :
  • (A) 90 à 110 parties en poids de magnésium, la source de magnésium étant présente sous la forme d'un hydrate de formule MgCl₂.n(H₂O) où n est un nombre réel supérieur à 0 et inférieur ou égal à 6, de préférence n est compris entre 2 et 6, et mieux de 3 à 11/2, avantageusement n est 6/2, 7/2, 8/2, 9/2, ou 10/2, et en particulier 9/2,
  • (B1) 180 à 190 parties en poids d'hydroxypropylméthylcellulose,
  • (B2) 19,8 à 22,2 parties en poids de béhénate de glycéryle,
  • (C1) 10 à 12 parties en poids de lactose, et
  • (C2) 10 à 12 parties en poids de silice colloïdale ; et,
• un enrobage de protection ralentissant la libération du magnésium au niveau gastrique, qui n'est pas gastrorésistant.

According to one particular aspect of the invention, there is provided a composition for oral administration of magnesium, in tablet form, with progressive release, a composition which comprises

• a matrix (forming in particular a nucleus) comprising:
  • (A) 90 to 110 parts by weight of magnesium, the magnesium source being present in the form of a hydrate of the formula MgCl ₂ .n (H ₂ O) where n is a real number greater than 0 and less than or equal to 6, preferably n is between 2 and 6, and preferably 3 to 11/2, advantageously n is 6/2, 7/2, 8/2, 9/2, or 10/2, and in particular 9 / 2
  • (B1) 180 to 190 parts by weight of hydroxypropylmethylcellulose,
  • (B2) 19.8 to 22.2 parts by weight of glyceryl behenate,
  • (C1) 10 to 12 parts by weight of lactose, and
  • (C2) 10 to 12 parts by weight of colloidal silica; and,
• a protective coating slowing the release of magnesium at the gastric level, which is not gastroresistant.

Description of the Figure

Figure 1 . Urinary elimination of magnesium expressed in mg over 24h after administration of two products: a product according to the invention to be released prolonged (2 tablets at 50 mg magnesium) and a reference product A immediate release (3 tablets at 100 mg magnesium).

Detailed description of the invention

Since magnesium absorption is all along the intestinal tract, from the duodenum to the large intestine, and is optimal at the level of the ileum (ie the last part of the small intestine), the duration of transit varies with the type meal, and as in the aforementioned dissolution system A at T = 2h there remains Mg administered not yet dissolved, an optimally absorbable amount of magnesium released (in the form Mg ²⁺ ) reaches according to the invention at the level of the ileum to cross the intestinal wall.

According to the invention a dissolution kinetics according to which the release of Mg occurs in a (i) relatively slow and (ii) progressive way from the 'gastric' phase. This kinetics has a particular dissolution in the stomach (which prohibits a gastroresistant film coating), on the one hand, and in the small intestine, on the other hand.

The matrix according to the invention and its coating do not include any product prohibited by European and international regulations relating to food supplements. In particular, said matrix and said coating are devoid of PCV and polyvinylpyrrolidone.

The substance B1 is hydroxypropyl methylcellulose (HPMC). It is used here in a quality that is suitable for pharmaceutical or food use.

B2 substance is glyceryl behenate, which is a mixture consisting essentially of monoglyceride and diglyceride of behenic acid (other nomenclature: 'mono-diglyceride behenate') and known under the European name of additive 'E471'. Substance B2 is also used here in a quality suitable for pharmaceutical or food use.

According to the invention, the weight ratio B1 / B2 is between 180 / 22.2 = 8.1 / 1 and 190 / 19.8 = 9.6 / 1. Advantageously, it is recommended that said report weighting is between 8.5 / 1 and 9.3 / 1. Preferably, the weight ratio B1 / B2 will be between 8.7 / 1 and 9.2 / 1, for example: 8.8 / 1 or 9/1 or even 9.15 / 1.

The lactose, component C1, is advantageously anhydrous. Similarly, the colloidal silica, component C2, is advantageously anhydrous. In practice, it is rather preferred that in the matrix of the invention the weight ratio C1 / C2 is close to 1/1 and better equal to 1/1.

1. (I) des comprimés à structure homogène contenant la totalité de la source de magnésium, ou
2. (II) des comprimés à structure composite (ou hétérogène) comprenant
   1. (a) une première structure (ou noyau 'interne') gastrorésistante, ou logée dans une enveloppe gastrorésistante, ladite première structure contenant 80 à 40 % du magnésium apporté par la source de magnésium, et
   2. (b) une seconde structure (ou couche 'externe') qui est hydrophile, qui se dissout au niveau de l'estomac et contient 20 à 60 % du magnésium apporté par la source de magnésium.

The composition comprising magnesium according to the invention may correspond to:

1. (I) homogeneously structured tablets containing the entire source of magnesium, or
2. (II) tablets with a composite (or heterogeneous) structure comprising
   1. (a) a first gastroresistant (or 'inner') structure, or housed in a gastroresistant envelope, said first structure containing 80 to 40% magnesium provided by the magnesium source, and
   2. (b) a second structure (or 'outer' layer) which is hydrophilic, which dissolves in the stomach and contains 20 to 60% of the magnesium supplied by the magnesium source.

The tablets used according to the invention further comprise a coating which is not enteric-resistant. This is a film coating that intervenes (i) to protect the components of the naked tablet vis-à-vis the outside, especially vis-à-vis shocks, and especially (ii) to slow the dissolution of Mg in the 'gastric' phase. This film coating can be made in a single layer, two layers or even three layers. To limit manufacturing costs, it is possible that it is monolayer. However, a two-layer coating is recommended, to better control the dissolution of Mg. As indicated above, the coating of the matrix generally represents 15 to 75 parts by weight for a magnesium source providing 90 to 110 parts by weight of Mg (ie approximately 1.3 to 7.5% by weight relative to weight of the matrix). Preferably, it will represent 15 to 70 parts by weight, and more preferably 15 to 45 parts by weight, for 90 to 110 parts by weight of Mg.

The substances recommended here for coating are shellac, and film-forming cellulose ethers such as alkylcelluloses, namely more particularly mixtures of HPMC and hydroxypropylcellulose (HPC) marketed in particular under the nomenclature of NUTRATERIC® and OPADRY® . It is also possible to envisage a coating consisting of a first layer of shellac and an outer layer made of a mixture of alkylcelluloses.

1. (a) un pelliculage monocouche de gomme laque (utilisée à 50 % en poids dans de l'éthanol, le solvant étant éliminé lors du pelliculage), ou
2. (b) un pelliculage à deux couches, chaque couche comprenant une substance choisie parmi la gomme laque, les éthers de cellulose (notamment HPMC et HPC) et leurs mélanges.

In practice, it is recommended a coating which is

1. (a) a monolayer film coating of shellac (used at 50% by weight in ethanol, the solvent being removed during the filming), or
2. (b) a two-layer film coating, each layer comprising a substance selected from shellac, cellulose ethers (especially HPMC and HPC) and mixtures thereof.

When using a two-layer coating, the first layer (or inner layer) generally represents 0.5 to 4% by weight relative to the weight of the matrix, and the second layer (or outer layer) generally represents 0.5 to 3.5% by weight relative to the weight of said matrix, all of said two layers representing 1.3 to 7.5% by weight relative to the weight of said matrix.

• d'une matrice (constituant en particulier un noyau) comprenant
  • (A) 90 à 110 parties en poids de magnésium, la source de magnésium étant MgCl₂.nH₂O, où n est un nombre réel supérieur à 0 et inférieur ou égal à 6, de préférence n est compris entre 2 et 6, et mieux de 3 à 11/2, avantageusement n est 6/2, 7/2, 8/2, 9/2, ou 10/2, et en particulier 9/2,
  • (B1) 180 à 190 parties en poids d'hydroxypropylméthylcellulose,
  • (B2) 19,8 à 22,2 parties en poids de béhénate de glycéryle,
  • (C1) 10 à 12 parties en poids de lactose, et
  • (C2) 10 à 12 parties en poids de silice colloïdale ; et
• d'un pelliculage de
  (D) 15 à 45 parties en poids d'une substance choisie parmi la gomme laque, les éthers de cellulose (notamment HPMC et HPC) et leurs mélanges.

According to the invention, a composition is recommended in the form of a film-coated tablet which releases magnesium gradually and continuously. This composition is advantageously constituted:

• of a matrix (constituting in particular a nucleus) comprising
  • (A) 90 to 110 parts by weight of magnesium, the magnesium source being MgCl ₂ .nH ₂ O, where n is a real number greater than 0 and less than or equal to 6, preferably n is between 2 and 6, and preferably from 3 to 11/2, advantageously n is 6/2, 7/2, 8/2, 9/2, or 10/2, and in particular 9/2,
  • (B1) 180 to 190 parts by weight of hydroxypropylmethylcellulose,
  • (B2) 19.8 to 22.2 parts by weight of glyceryl behenate,
  • (C1) 10 to 12 parts by weight of lactose, and
  • (C2) 10 to 12 parts by weight of colloidal silica; and
• filming of
  (D) 15 to 45 parts by weight of a substance selected from shellac, cellulose ethers (especially HPMC and HPC) and mixtures thereof.

It is recommended to keep the composition used according to the invention at a temperature below 40 ° C, and preferably at a temperature of less than or equal to 25 ° C.

The composition comprising magnesium is used according to the invention in combination with a composition intended to treat type 2 diabetes or its complications.

The composition for treating type 2 diabetes or its complications is according to a particular embodiment of the invention a composition for oral administration.

It comprises in a pharmaceutically acceptable medium at least one pharmaceutical active agent for treating type 2 diabetes, or its complications.

The pharmaceutical active ingredient for treating type 2 diabetes may be chosen from insulin secretion stimulating agents, insulin sensitizers, glucogenesis reducing agents, dipeptidyl peptidase 4 inhibitors and inhibitors of alpha-glucosidase.

The agents stimulating the secretion of insulin may be chosen in particular from sulfonylureas and "glinides". By way of example of sulphonylureas, there may be mentioned in particular carbutamide (Glucidoral®), glibenclamide / glyburide (Daonil®, Euglucan®), glibomuride (Glutril®), gliclazide (Diamicron®), glimepiride (Amarel ®), glipizide (Glibenesis®). As an example of "glinides", mention may in particular be made of repaglinide (NovoNorm®).

Glucose-lowering agents are generally represented by biguanides, and metformin (Glucophage®, Stagid®) may be mentioned in particular.

Among the inhibitors of dipeptidyl peptidase 4 include saxagliptin, sitaglyptine, and vidagliptin.

Insulin sensitizers are mainly represented by thiazolidinediones (TZDs). In particular, pioglitazone (Actos®) or rosiglitazone (Avandia®) may be mentioned.

Among the alpha-glucosidase inhibitors, mention may in particular be made of acarbose (Glucor®) or miglitol (Diastabol®).

Diabetic patients are also known to be at risk for the development of cardiovascular diseases, particularly atherosclerosis. This is partly due to increased susceptibility to factors such as hyperlipidemia or hypercholesterolemia. Thus, the reduction of low density lipoprotein cholesterol (LDL-cholesterol) in the serum is the first therapeutic approach. It may also be important to identify patients with low HDL cholesterol and / or high triglyceride levels. In particular, it has been shown that triglyceride-rich lipoproteins from either the liver (VLDL) or the intestine (chylomicron) present a significant atherogenic risk.

According to one particular embodiment of the invention, the composition intended for treating type 2 diabetes or its complications may comprise a pharmaceutical active agent chosen from compounds which lower the level of lipids or of cholesterol, such as, in particular, PPARalpha agonists, in particular fibrates (eg, fenofibrate, bezafibrate, ciprofibrate, or gemfibrozyl), HmGCoA inhibitors (Hydroxymethylglutaryl Coenzyme A reductase), such as statins (eg, atorvastatin, simvastatin, or fluvastatin), inhibitors of absorption of cholesterol (for example: ezetimibe, or phytosterols), inhibitors of CETP (Cholesteryl Ester Transfer Protein), such as torcetrapib, ACAT inhibitors (AcylCoA-Cholesterol Acyl Transferase), MTP inhibitors ( Microsomal Triglyceride Transfer Protein), sequestering agents of bile acids (cholestyramine), etc.

According to another particular embodiment of the invention, the composition intended to treat type 2 diabetes or its complications may comprise a pharmaceutical active agent chosen from antihypertensive and hypotension agents, ACE (Angiotensin-Converting Enzyme) inhibitors (eg, captopril, enalapril, ramipril or quinapril), angiotensin II receptor antagonists (eg, losartan, valsartan, telmisartan, eposartan, irbesartan, etc.), beta blockers (atenolol, metoprolol, labetalol, propranolol), diuretics (for example: furosemide, indapamide, hydrochlorothiazide, or anti-aldosterone), vasodilators and alpha receptor blocking agents (such as prazosin or urapidil) or minoxidil, calcium channel blocking agents (eg, nifedipine, felodipine, amlodipine, diltizem or verapamil), etc.

The composition for treating type 2 diabetes or its complications may comprise at least two pharmaceutical active ingredients for treating type 2 diabetes or its complications. Thus, a composition for treating type 2 diabetes or its complications may comprise, in the same pharmaceutical form or in separate pharmaceutical forms, metformin and a sulfonylurea, a biguanide or a thiazolidinedione. Examples of combinations of active ingredients are: metformin + glibenclamide / glyburide, metformin + glipizide, metformin + pioglitazone, metformin + rosiglitazone, metformin + sitagliptin, and metformin + vidagliptin. Also, a composition intended to treat type 2 diabetes or its complications may comprise, optionally in the same pharmaceutical form or in several pharmaceutical forms, at least one therapeutic agent for treating type 2 diabetes, as defined above, in particular selected from insulin secretion stimulating agents, insulin sensitizers, glucogenesis reducing agents, alpha-glucosidase inhibitors, and at least one antihypertensive or hypotensive agent, as defined above, such as angiotensin II receptor antagonists.

Many pharmaceutical products to treat type 2 diabetes are already on the market. They are usually administered orally.

The present invention thus makes it possible to treat, in particular to reduce the effects of type 2 diabetes, and / or to treat at least one of its complications, by particularly cardiovascular diseases, hypertension, retinopathy, nephropathy, depression and / or diabetic foot ulcers.

According to a mode of the invention, said compositions are administered simultaneously, separately or spread over time. The compositions can therefore be administered simultaneously (but separately), or sequentially.

The term "sequential" means a time-separated application of the composition comprising magnesium and the pharmaceutical composition comprising at least one pharmaceutical active agent for treating type 2 diabetes or its complications. The user can therefore successively administer the composition comprising magnesium, and the pharmaceutical composition comprising at least one pharmaceutical active ingredient for treating diabetes or its complications, after a few seconds or after several hours in the same day, especially in an interval ranging from 1 hour to 3 days. According to an alternative, the composition comprising the pharmaceutical active agent for treating type 2 diabetes or its complications is administered firstly, and secondly the composition comprising magnesium. According to another alternative, the composition comprising magnesium is first administered, and secondly the pharmaceutical composition comprising at least one pharmaceutical active ingredient for treating type 2 diabetes or its complications.

The pharmaceutical composition comprising at least one active pharmaceutical for treating type 2 diabetes or its complications will be administered, preferably orally, according to the prescribed treatment, and in particular this treatment will depend on the asset or assets administered and the patient .

The composition comprising magnesium and described above generally comprises between 50 mg and 100 mg of magnesium. This composition is administered so that 100 to 200 mg of magnesium per day is administered to the subject. Advantageously, one to ten tablets are administered per day, for example in the morning and / or evening, preferably in the morning or in the morning and in the evening. According to one embodiment, it may be administered one or two tablets, or even up to 4 or 5 tablets, once or twice a day. According to another particular embodiment, when the tablet comprises 50 mg of magnesium, two to four tablets may be administered daily, preferably in the morning and / or evening, preferably two to four tablets only in the morning or alternatively one or two in the morning and one or two in the evening. According to another particular embodiment, when the tablet comprises 100 mg of magnesium, one to two tablets may be administered per day, preferably in the morning and / or evening.

In one embodiment, the term "treatment" or "treating" refers to an improvement or prophylaxis of type 2 diabetes or in particular one of its complications. In another embodiment, "treatment" or "treating" means an improvement, prophylaxis, or reversal of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible. at or by the subject treated. In another embodiment, "treatment" or "treating" refers to the inhibition or slowing of progression of type 2 diabetes or one of its complications. In another embodiment, "treatment" or "treating" means delaying the onset of at least one of the complications of type 2 diabetes, particularly cardiovascular diseases (such as cardiac arrhythmias, arteritis , atherosclerosis), hypertension, retinopathy, nephropathy, depression or diabetic foot ulcer. In particular, in the case of diabetic foot ulcer, the present invention may be adapted to prevent, delay the onset, or decrease the risk of developing a diabetic foot ulcer.

In one embodiment, the compositions are administered as a curative measure. In the present context, "curative" means reducing the effects of type 2 diabetes and / or reducing the development or worsening of any of the complications of type 2 diabetes, particularly cardiovascular diseases (such as heart rhythm, arteritis, atherosclerosis), hypertension, retinopathy, nephropathy, depression and foot ulcers, and more specifically cardiovascular diseases (such as heart rhythm disorders, arteritis, atherosclerosis), hypertension, retinopathy, nephropathy, depression.

The present invention also relates to a method of treating type 2 diabetes or one of its complications, in which a subject suffering from type 2 diabetes and possibly one of its complications is administered a composition comprising magnesium as defined above in combination with a pharmaceutical composition comprising at least one pharmaceutical active for treating type 2 diabetes or its complications, said compositions being administrable simultaneously (but separately), or sequentially.

For the purposes of the present invention, the term "patient" or "subject" means any mammal, and more particularly human beings, men or women.

Other advantages and features of the invention will be better understood on reading the following examples. Of course these examples are not limiting in nature, they are given for illustrative purposes only.

The tests relating to the determination of the dissolution kinetics of Mg were carried out at 40 ° C. in vitro using the aforementioned system A: 0.1N HCl medium of T = 0 at T = 2h, then buffer medium at pH 6.8 from T = 2h to T = 8h.

Example 1

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.15 / 1), Qt / cp representing the amount (expressed in mg) of each tablet component. constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 183.0 Mono-diglyceride behenate 20.0 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating : Shellac 39.6 Total : 989.60

The dissolution profile of these tablets is as described in the present invention.

Tablets equivalent to those detailed above were prepared with MgCl ₂ .6 / 2H ₂ O and MgCl ₂ .7 / 2H ₂ O.

Example 2

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.35 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 185.2 Mono-diglyceride behenate 19.8 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating: Shellac 39.42 Patent blue 0.03 Total : 992.45

The dissolution profile of these tablets is as described in the present invention.

Tablets equivalent to those detailed above are prepared with MgCl ₂ .10 / 2H ₂ O and MgCl ₂ .8 / 2H ₂ O.

Example 3

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.25 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 185.0 Mono-diglyceride behenate 20.0 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating: Shellac 39.6 Total : 991.60

The dissolution profile of these tablets is as described in the present invention.

Tablets equivalent to those detailed above were prepared with MgCl ₂ .6 / 2H ₂ O and MgCl ₂ .7 / 2H ₂ O.

Example 4

Tablets (dosed at 100 mg magnesium) having the following formulation were prepared according to the aforementioned modalities (the weight ratio B1 / B2 being 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 183.0 Mono-diglyceride behenate 20.0 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating 1 : Shellac 24,17 Laminating 2 : HPMC / HPC blend 1/3 w / w 17.514 Patent blue 0.016 Total : 991.70

The dissolution profile of these tablets is as described in the present invention.

Tablets equivalent to those detailed above are prepared with MgCl ₂ .7 / 2H ₂ O and MgCl ₂ .10 / 2H ₂ O.

Example 5

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 183.0 Mono-diglyceride behenate 20.0 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating: ^1st layer: Shellac 19.8 ^2nd layer (external) : HPMC / HPC blend 1/4 p / p 19.8 Total : 989.60

The dissolution profile of these tablets is as described in the present invention.

Example 6

Prepared according to the modalities of Example 5, tablets containing 50 mg of magnesium and having for each component an amount which is half that of the homologous component of said Ex 5.

Example 7

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 183.0 Mono-diglyceride behenate 20.0 Anhydrous lactose 11.0 Anhydrous colloidal silica 11.0 Laminating : ^1st (inner) layer: HPMC / HPC 1/3 p / p 19.8 ^2nd layer (external) : HPMC / HPC blend 1/4 p / p 19.8 Total : 989.60

The dissolution profile of these tablets is as described in the present invention.

Tablets equivalent to those detailed above were prepared with MgCl ₂ .6 / 2H ₂ O and MgCl ₂ .7 / 2H ₂ O.

Example 8

Prepared according to the method of Example 7, tablets containing 50 mg of magnesium and having for each component an amount which is half that of the homologous component of said Ex 7.

Example 9

Tablets (100 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 8.8 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 725.0 HPMC 190.0 Mono-diglyceride behenate 21.5 Anhydrous lactose 10.0 Anhydrous colloidal silica 10.0 Pyridoxine hydrochloride 6.0 Laminating: Shellac 40.0 Total : 1003.0

Example 10

Tablets (50 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 362.50 HPMC 91.50 Mono-diglyceride behenate 10.00 Anhydrous lactose 5.50 Anhydrous colloidal silica 5.50 Laminating 1 : Shellac (OPAGLOS® NA715G, product marketed by the so-called COLORCON) 1.3 to 2.2% * Laminating 2 : HPMC / HPC mixture 1/3 w / w (OPADRY® VMS, product marketed by the so-called COLORCON) 1.1 to 1.6% * Yellow 20A38069 0,008 Note (*): percentage by weight relative to the weight of the naked tablet.

Example 11

Tablets (50 mg magnesium) having the following formulation were prepared (the B1 / B2 weight ratio was 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 362.50 HPMC 91.50 Mono-diglyceride behenate 10.00 Anhydrous lactose 5.50 Anhydrous colloidal silica 5.50 Laminating: Shellac (OPAGLOS® NA715G, product marketed by the so-called COLORCON) 1.7% * Note (*): percentage by weight relative to the weight of the naked tablet.

The dissolution profile of these tablets is as described in the present invention.

Example 12

Tablets (50 mg magnesium) were prepared having the following formulation (weight ratio B1 / B2 being 9.15 / 1). constituents Qty / cp (mg) Core : MgCl ₂ .9 / 2H ₂ O 362.50 HPMC 91.50 Mono-diglyceride behenate 10.00 Anhydrous lactose 5.50 Anhydrous colloidal silica 5.50 Laminating 1 : Shellac (OPAGLOS® NA715G, product marketed by the so-called COLORCON) 1.7 * Laminating 2: 1/3 w / w HPMC / HPC blend (OPADRY® VMS, product marketed by the so-called COLORCON) 0.5% * Note (*): percentage by weight relative to the weight of the naked tablet.

Example 13

The objective of the clinical study was to evaluate the relative bioavailability of magnesium provided by two formulations administered orally:
2 tablets containing 50 mg of magnesium chloride (magnesium chloride), such as those described in Example 12, according to the invention, ie 100 mg of magnesium element, versus a product of reference Product A (3 tablets at 100 mg of magnesium, immediate release), or 300 mg of magnesium element.

The randomized clinical trial was conducted in double-blind and cross-over on healthy subjects (men). Each of the volunteers who participated in the study received both products under study, with a 48-hour window (wash-out) between the two supplementation periods.

In order to evaluate the bioavailability, a urine magnesium assay collected between 0 and 24 hours after taking the tablets was performed to measure the amount of magnesium eliminated by the body. A standardized diet provided the same amount of magnesium to all subjects.

RESULTS

All subjects were included in the statistical analysis of the results because no atypical or aberrant data were revealed which would have justified to exclude them from the analysis.

The primary endpoint of the study was the comparison of the total magnesium distribution present in the subject's body, that is, the subject's "basal" magnesium supplemented with magnesium. the tablets of Example 12 and in the urine, versus the reference product.

The urinary elimination of magnesium, measured on samples collected sequentially during the 24 hours after setting, showed homogeneous results, with a power of between 73.3% (T0-T5h) and 96.8% (T0). -T24h).

After 24 hours, the cumulative urinary elimination of magnesium (that is to say, magnesium "basal" plus magnesium absorbed) is, following the consumption of 100 mg of magnesium element provided by the tablets according to the invention, of 100.53 mg while it is 117.68 mg after consumption of 300 mg of magnesium component provided by reference product A.

Urinary magnesium

The urinary excretion of magnesium, measured on samples collected sequentially during the 24 hours after taking the product, shows consistent results.

The statistical power of this study is between 73 and 97% which means that the number of subjects was sufficient to see the possible differences between treatment groups.

These results, presented cumulatively on the Figure 1 , Show that the product according to the invention with magnesium intake of 100mg, that is to say 3 times lower than those of the reference product A (300 mg) provides a very close urinary excretion of magnesium of that of Product A, the 200mg difference between the two doses is not absorbed and is likely eliminated in the feces.

The absorption efficiency of magnesium is therefore better with the product according to the invention than with the reference product.

CONCLUSION

In this study based on the comparison of the urinary elimination of magnesium (reflection of intestinal absorption), the results indicate that the formulation according to the invention makes it possible to obtain a better "bioavailability" of magnesium administered orally relative to to the formulation of Product A.

Better bioavailability - better absorption efficiency

The results of the study show that the amounts eliminated by the urinary route are almost identical with the 100 mg provided by the product according to the invention and with the 300 mg provided by Product A, and suggests that the absorption efficiency is three times higher with the formulation according to the invention and that the difference (about 200 mg) was not absorbed and therefore was eliminated by the faecal route.

.Improved intestinal tolerance

The greater the amount of magnesium released in the intestine, the greater the potential for irritation of the intestine due to unabsorbed magnesium ions. This irritation can lead to possible digestive disorders such as: stomach ache, diarrhea, nausea, etc. Thus, the product according to the invention by its low dosage and better absorption efficiency should greatly reduce these risks of adverse effects.

Better bioavailability due to the formulation according to the invention

The 100 mg of magnesium provided by the formula according to the invention are found in the urine collected during the 48 hours following the setting, which suggests a excellent bioavailability, able to maintain optimal magnesium in the long term.

The formulation according to the invention administered at the dose of 100 mg, in comparison with the Reference Product at a dose of 300 mg, thus allows a better bioavailability, and a better digestive tolerance of magnesium, which is particularly advantageous for subjects presenting or likely to have type 2 diabetes or at least one of its complications. The formulation according to the invention makes it possible for almost all the swallowed Mg to be assimilated by the body for amounts 3 times lower than the reference product, which makes it possible to obtain better intestinal and renal tolerance.

Example 14

Pharmaceutical compositions for oral administration comprising at least one pharmaceutical active ingredient for treating type 2 diabetes are, for example, chosen from those mentioned above and sold in particular under the trademarks: Glucophage®, Metformin Biogaran®, Stagid®, Galvus® (active DCI) : Vidagliptin), Glucidoral ® (active DCI: Carbutamide), Daonil (active DCI: Glibenclamide), Amarel ® (active DCI: Glimepiride), Diamicron ® (active DCI: Glicazide), NovoNorm ® (active DCI: repaglinide), Actos ® (Active INN: pioglitazone), Avandia® (active DCI: rosiglitazone), Glucor® (active DCI: acarbose), or Diastabol® (active DCI: miglitol), or asset combinations, such as Glucovance ® (DCI active ingredients: metformin + glibenclamide), Competact ® (active DCI: metformin + pioglitazone), Janumet ® (active DCI: metformin + sitagliptin), Eucreas ® (active DCI: metformin + vidagliptin).

These products can therefore according to the invention be administered according to the prescription of the doctor in combination with the tablets described in one of Examples 1-12. Preferably, these magnesium-containing products are administered such that 100-500 mg of magnesium is administered per day to the subject. Advantageously one to ten tablets are administered per day, for example in the morning and / or in the evening, preferably in the morning or in the morning and in the evening. according to an embodiment, it may be administered one or two tablets, or even up to 4 or 5 tablets, one to two times a day. According to another particular embodiment, when the tablet comprises 50 mg of magnesium, from two to four tablets may be administered per day, advantageously in the morning and / or evening, preferably from two to four tablets only in the morning or alternatively one or two in the morning and one or two in the evening. According to another particular embodiment, when the tablet comprises 100 mg of magnesium, one to two tablets may be administered per day, preferably in the morning and / or evening.

Claims (13)

1. A composition comprising magnesium, for use in the treatment of type 2 diabetes or one of the complications thereof, in combination with a pharmaceutical composition comprising at least one active agent intended for treating type 2 diabetes, said composition comprising magnesium being a composition for oral administration, in tablet form, comprising a gradual-release magnesium matrix comprising magnesium, a hydrophilic delay agent (B1), a hydrophobic delay agent (B2), an inert filler (C1) acting as a diluent and an inert filler (C2) acting as a lubricating means, said matrix being characterized in that it comprises:

   (A) 90 to 110 parts by weight of magnesium, the magnesium source being present in the form chosen from MgO, MgCl₂ and the hydrates of formula MgCl₂.n(H₂O) where n is a whole or fractional real number greater than 0 and less than or equal to 6,

   (B1) 180 to 190 parts by weight of hydroxypropylmethylcellulose,

   (B2) 19.8 to 22.2 parts by weight of glyceryl behenate,

   (C1) 10 to 12 parts by weight of lactose, and

   (C2) 10 to 12 parts by weight of colloidal silica;

   said composition also comprises a coating, which is not a gastroresistant coating, but a protective coating which slows down the dissolution of the Mg at the gastric level and said composition comprising magnesium is administered such that 100 to 200 mg of magnesium are administered per day to the subject.
2. The composition for use according to claim 1, characterized in that said coating is a film-coating with one or more layers.
3. The composition for use according to claim 2, characterized in that said coating represents 1.3% to 7.5% by weight relative to the weight of the matrix.
4. The composition for use according to claim 3, characterized in that said coating is

   (a) a monolayer film-coating of shellac, or

   (b) a two-layer film-coating, each layer comprising a substance chosen from shellac, cellulose ethers, and mixtures thereof.
5. The composition for use according to one of the preceding claims, said composition comprising magnesium corresponding to:

   (I) tablets with a homogeneous structure containing all of the magnesium source, or

   (II) tablets with a composite structure comprising

   (a) a first structure (or 'internal' core) which is gastroresistant, or housed in a gastroresistant shell, said first structure containing 80% to 40% of the magnesium provided by the magnesium source, and

   (b) a second structure (or 'external' layer) which is hydrophilic, which dissolves in the stomach and contains 20% to 60% of the magnesium provided by the magnesium source.
6. The composition for use according to one of the preceding claims, said composition being made of:

   • of a matrix comprising

   (A) 90 to 110 parts by weight of magnesium, the magnesium source being MgCl₂.nH₂O, where n is a real number greater than 0 and less than or equal to 6, preferably n is between 2 and 6, and better still from 3 to 11/2, advantageously n is 6/2, 7/2, 8/2, 9/2 or 10/2, and in particular 9/2,

   (B1) 180 to 190 parts by weight of hydroxypropylmethylcellulose,

   (B2) 19.8 to 22.2 parts by weight of glyceryl behenate,

   (C1) 10 to 12 parts by weight of lactose, and

   (C2) 10 to 12 parts by weight of colloidal silica; and

   • of a film-coating of
   (D) 15 to 45 parts by weight of a substance chosen from shellac, cellulose ethers, and mixtures thereof.
7. The composition for use according to one of the preceding claims, said compositions being administered simultaneously, separately or in a manner spread out over time.
8. The composition for use according to one of the preceding claims, the composition intended for treating type 2 diabetes or complications thereof comprising, in a pharmaceutically acceptable medium, at least one pharmaceutical active agent intended for treating type 2 diabetes, said active agent being selected from agents which stimulate insulin secretion, insulin sensitizers, agents which decrease glucogenesis, dipeptidyl peptidase-4 inhibitors and alpha-glucosidase inhibitors.
9. The composition for use according to one of the preceding claims, the composition intended for treating type 2 diabetes or complications thereof comprising at least two pharmaceutical active agents intended for treating type 2 diabetes or complications thereof.
10. The composition for use according to one of the preceding claims, with a view to a decrease in the effects of type 2 diabetes, and/or to a treatment of at least one of the complications thereof, in particular cardiovascular diseases, hypertension, retinopathy, nephropathy, depression and/or diabetic foot ulcers.
11. The composition for use according to one of the preceding claims, with a view to delaying the appearance of at least one of the complications of type 2 diabetes, in particular cardiovascular diseases, hypertension, retinopathy, nephropathy, diabetic foot ulcer or depression.
12. The composition for use according to one of the preceding claims, with a view to decreasing the development or the worsening of one of the complications of type 2 diabetes, in particular cardiovascular diseases, hypertension, retinopathy, nephropathy, depression and foot ulcers, and more specifically cardiovascular diseases, hypertension, retinopathy, nephropathy and depression.
13. The composition for use according to one of the preceding claims, the composition which comprises magnesium comprising from 50 mg to 100 mg of magnesium per tablet.

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